Halogenated (2-thenoyl)-o-benzoic acids



' halogenated thiophene.

Patented July 4, 1950 2,513,572 a I ,HALOGENATED (2-THENOYL)-0-BENZOIQ a ACIDS Henry R. Lee and Viktor Weinmayr; Pitman, N. J assignors to E. I. du 'Pont. de Nemours &

Company, Wilmington,

Delaware N Drawing. Application January Serial No.-7-23,669

3Claims. (omen-429)) I This invention relates to the'preparation of new halogen-substituted (Z-thenoyD-o-benzoic acids, and more particularly to the preparation of the chloroand bromo-substituted compounds 'of the formula:

,6 coon A 4 C/LS; k iii) in which the h'alogen in one or more of the positions 3, 4, 5 and 6 are substituted by chlorine or'bromine. a v I a; It is an object of this invention to prepare a new intermediate compound suitable'for further condensation or reaction, particularly in the preparation of' new dyes. A. further object of the invention is to provide a commerciallyfea-tego sible process for the preparation of these new halogen-containing compounds.

While in the preparation of the corresponding benzoyl benzoic acids the Friedel-Crafts condensation of halogenated phthalic anhydrides withbigs' benzene takes place even more readily than the condensation of the unsubstituted phthalic anhydride with benzene, it was found that the halogen-substituted compounds of the pre'sentinvention could not be produced satisfactorily by the Friedel-Crafts-condensation of thehalogenated phthalic anhydrides-with thiophene.

The new compounds of the present'inven'tion may be prepared in. good yields and purity by reacting halogenated phthalic anhydrides with,;,,35 the Grignard reagent prepared from the alpha Because of the unsymmetrical configuration of thiophene, two isomeric halogenated (2-thenoyll o-benzoic acids are frequently obtained, but these may be separated gw by crystallization, selective acidification of their salt solution, or by taking advantage of the differing solubilities of their salts. The Grignard reagent employed in the process of this invention may be made from either the dfi Example 1 The preparation of the Grignard reagent, and

the subsequent condensation with 3,6-dich1oro 55 of anhydrous'ether, Asolution oi 1.9 parts oigfi Del., a corporation of alpha-bromothiophene' -in Sil -parts of anhydrous ether was prepared; a small fraction of this solution was added to themagnesium charge and heat was applied to-start-thereaction As soon asrthe reactionset the agitation was-started and the alpha-bromothiophene'solution was added during about one hour at such a ratethat vigorous refluxing, indicating a satisfactory rate of reaction, continued. Depending upon the charge size, more or less external cooling was-required during'that addition. The charge was refluxed for an addi tional one to two hour sv (charge temperature from 30 to 368C.) and then cooled to belo w gii? C.

Sixty-five (65) parts .of 3,6-dichloro 'p hthalic anhydride was dissolved in 1400 partsof drybenzene and the temperature o'f thesolution was raised to 50? o. The unfilteredGrignard reagent,

as obtained above, was addedto. the well-agitated 3,6-dichlorophthalic anhydride solution in about one minute. The temperature of the chargerose -from 50 to 58 C., and a milkyewhite precipitate wasformed, The reaction mass was refiux edat a charge temperature of 60? C, for about one, hour and then,.c0oled to aboutZO? c. Five'hundrd v-(500) parts of. cold'water were gradually added at from to C. and. the chargewas refluxed again for about oneho' ur. ,Ten (lfll part of magnesium oxide were then added to make er- .tain that all .acids were converted to the jrnagnesium salts, nd a ation.wa r 'enue several hours, while the temperaturewas he at 20 to 25 C. I v The benzene-etherlayer Was separated by gravity from the slightly alkalineflaqueous layer. oily precipitate, WhichsOIidifiedupOn standing, was formed when the ,,water, layer was n de strongly acidwithhydrochloric acid.

Sixty-seven (6'7) parts of crude 3,6 -dich lor. ,o- (Z-thenoyD-o-benzbic acidwere obtained, equal to a 'yield of 74.4% basedongthe alpha brompthiophene. The product was regpdilycrystallized from about 2.5 partsof benzene perjpart of crude product, andwas then obtained as white crystals melting at ,lfi-146f C. The colorof itsjsulfuric acid solution was yellow. I; ,i

ta he3fir hlaii" Acetic acid-did not PR9. i, I v (2-thenoyl)-o-benzoic acid from its magnesium or sodium salt solutions.

' Example 2 Iv The Grignard reagent was prepared as in Example 1 from 14 parts of magnesium turnings, 500 parts of anhydrous ether and- 84-- parts;;of 'alnha-bromothiophene. The Grignard reagent. was poured into a suspension of 143 parts of. tetrachlorophthalic. an-

. hydride in 1400 partsof benzene ata temperature of-from 45 to- C. The charge wasrefluxed about two hours,- and treated with about SOOIp'aijts of water as described in Example, 1. The magnoyD-o-benzoic acid was very insoluble'in" the water and was isolated by filtration. About 9% of unreacted tetrachlorophthalic-acid Wasisolated from the aqueous filtrate. r

The filter cake of the 3,4,5,6-tetrachloro- (2- thenoyD-o-benzoic acid was s'lurried in "1000 parts of 90 C. water andhydro'ch'l'oric acidiwas added until the charge was-etrsfi'g'n acid. The

crystalline precipitate changed to an oil and crystallized again as the free acid af t -a short.

The precipitate was filtered at -'25 C.-, washed mineral acid-free and dried. One hun time.

. "Emma-3 The .Gi'ig'nard reaee it'wasrsrepared ijas Ex *nispgftstr nragnesinm turning/900 p rts of eher anazesiia er alpha-bromot igphene." slut Was'ad'dedtoa s'olution an 27.4 parts of freshly distilled 3 chloro''phtha1ic a hyd ide-incont-am6f benzene held at jjjtdc The charge, containing a'whiteprecinb f tatefwas refluxed at meme-Brawn of from 1-,Q"'60 -C. "for ab'c'iuttwehoiirs. Fiv 'h'und'red jjisoogtparts'or wate andem part qr magnesium Sc idefwereaddedand refluxing wascontmued pr sveral Hours. "The .rea'tien *mass' was then e1- ;.tefe'd at roiififteniperature; arid-the light colored, fis layr lontaifiifi'g "the two 'isor'neric 'lcliloiol2 thenoyl)-o-benzoic acids was sa -a fated. I

, {two isorners 3. "re separated rom each .ptherby. acidifyina the "nous fir's't with acetic acid; "then with hydro- 'tio'n until no" further'precipitate "was term-ea lv'e"(12) parts of-a, crude 6 'ch'l'oro (2-then- "Sim -o b'enzoi'c"'acid' wereformed, n elting at from "U on crystallizationlfrom iz'r arts er chlcroben- "Cities obtained. k

'l rh e acetic'aci'rl"filtrate"fromabove was"acidi- :fi'dwithhydiochloric"acid until'no further re- "ci iitate "wasrormea. Fourteen (14) parts of A cing theknown e-nitm-ta-tn nbyn ofbeflz'oic aicidlsee Example '2 of co pending application "noyD q-b'erfzoic acids wasie'stablished by re- *SerialfiNof-x'i2i6i0) to the"-"6a1n i1io 2-then0yl) 'o b'enzj'oic "acid, 'diazot'i'z'ing the latter and converting it to the 6-chloro-(2-thenoyl)-o-benzoic acid by the Sandmeyer reaction. The 6-ch10roa I2-th'enoylr o benzoic acid thus obtained melted "Example 4 The Grignardreaction was carried out as describedin'the preceding examples, using 9 parts of magnesium turnings, 250 parts of ether and 63tia 'rts'bf alphadodothiophene. The Grignard solution was poured into a solution of 61 parts -of e chlorophthalicanhydride in 1100 parts of "benzene,- at a temperature "of "40 to 50 0., and "a whiteprecipitate formed at once. The charge was refluxed 'fo'r several hours, then 'diluted"w'ith 750 parts of water, refiuxed'again'and filtered. The two isomeric chloro-( 2-thenoyl)-o-benzoic acids thus obtained were "separated from each other by acidifying: their magnesium salt. solution first withkacetic acid, then with hydrochloric acid. I 7

Thus, by adding acetic acid to the aqueous layer of the filtrate a crystalline precipitate was obtained which, after filtering, washing anddrying amounted to 42 parts; equal to a yield of 47.3% of theory. It had a melting range offrom 176 to 193f-C. The product was rather insoluble in chlorobenzene but was readily crystallized v.frcrn nitrobenzene. using-- 2.5 .parts of solventper part of crude, giving the pure '5-ch1oro-(2- 35 thenoyl) -0-b enzoic acid-in theshape of whit crystals-melting at 22 5-226'C.

The acetic acid filtrate-from the aboveisomer was-made strongly acid with hydrochloric'zacid, and- 12 parts of 4-ch1oro-(2-thenoyl) o-benzoic 4 'a'cidm'elting at H P-146 Cjwere obtained, equal to a yield of 13.5% of theory. This'productwas much more soluble .inichlorobenzene than' the 5- chloro isomer and was crystallized from =2 parts of solvent per part of" product, giving the-pure 4-chloro-- 2*thenoyl)'+obenzoic acid melting at -154'155C. "Both isomeric chlor'o-(2 thenoyD o-benzoic .acids'were soliible in sulfuric acid with yellowcolor.

. The constitution of "these two chlor'o-(Z- 'thenoyll-o-benzoic acids was" established byreducing the known 5-nitro- (2-thenoy1) -o--benzoic -a'cid'of 'co pending apphc'ation'SeriaYNo. 723,670 to the 5=amino(2-'then'oyl) -o-benzoic acid, diaz'otizing the latter, "and converting it to the '5-chloro-(2-thenoyl) -o"-benzoic "acid by the 'Sandmeye'r reaction. The-'S-ehloro- (2-the'n'oyl) 'o benzo'ic acid thus obtained'melted at -2 25- 226 C. The chloro- (Z-th'enoyl) '-'o -ben'zo'ic acid rnelting at -154'-155 C. 'c'an therefoie only bethe 4- hl'oro (2-thenoyl) -'o-ben"zoic acid.

Example 5 The Grignard reagent was prepared as described in the preceding'examples; using 400parts bf-etherpi) parts of "ma'gnesium turning's and 49 parts of'alpha-bromotliiophene. .It'wasaddedto a suspension of parts of 3,4-dichlorophthalic v anhydride in 1100 partsofbenzene at from 45 to 50 ovover'a pened or 5'i'fiini1t'es. The'ch'argewas refluxed ier-severalnears'j izso parts of Water were added, and heating to abo1'1t5'0 Cfw'as continued for'sev'eral hears longer; *Theehargewas -thenfiltered'iatabout25 c. p

A penny sombmmagne'sium salt ofthe erm- 76 denls'ation' product was retained o'n "the 'filter funnel, while the aqueous layer of the filtrate contained a soluble magnesium salt.

The insoluble fraction was slurried in 1000 parts of .hot water, acidified with hydrochloric acid, and the precipitate thus formed dissolved in about 1000 parts of dilute sodium carbonate. This solution was filtered and acidified with acetic acid. A white, crystalline precipitate was formed amounting to parts, equal to 16.6% of theory as dichloro-(2-thenoyl)-o-benzoic acid, melting from 199-201 0. About half a part more of the same isomer, melting from 194-19'7 C., was obtained by acidifying the acetic acid filtrate with hydrochloric acid, making the total yield of this isomer 17.2% of theory. By crystallizing one part of crude product from 5 parts of chlorobenzene, a pure dichloro-(Z-thenoyD- o-benzoic acid, melting at 202203 C., was obtained.

The aqueous solution of the magnesium salt of the original separation of the condensation mass was acidified first with acetic acid, giving 17 parts of dichloro-(Z-thenoyl) -o-benzoic acid melting at 152-153 C.; then the acetic acid filtrate was acidified with hydrochloric acid, giving 20 parts of dichloro-(Z-thenoyl)-o-benzoic acid melting from 156 to 159 C. Both fractions proved to be identical. Thus, in this case the separation of the isomers was already accomplished by the solubility of their magnesium salts in water. The total yield of the second isomer, which melted at l66-16'7 C. after crystallizing it from 2.5 parts of chlorobenzene per part of crude product, was 40.9% of theory.

Example 6 The Grignard reagent was prepared as in Example 1 from 27 parts of alpha-bromothiophene,

6 parts of magnesium and 600 parts of ether. This solution was poured into a solution of 44.5 parts of 4-bromophthalic anhydride in 800 parts of benzene over a period of 5. minutes at a temperature of from 30 to 37 C. A creamy white precipitate was formed and the reaction mass was heated to reflux for one hour. Five hundred (500) parts of water and about one part of magnesium oxide were added, and refluxing was continued for about one hour.

The solvent layer was then separated from the water solution of the magnesium salt of the bromo-(Z-thenoyl)-o-benzoic acids. The water layer was acidified with acetic acid until no further precipitate was formed. 21.2 parts of a crude bromo-(Z-thenoyl) -o-benzoic acid melting from 198-212 C. were obtained, equal to a yield of 42.5% of theory. After crystallizations from 10 parts of chlorobenzene per part of crude keto acid, a pure bromo-(2-thenoyl)-o-benzoic acid, melting at from 224-226 C., was obtained.

The acetic acid filtrate was acidified with hydrochloric acid. A pale yellow oil was precipitated, which solidified to a crystalline product after several hours. 3.8 parts of a crude bromo- (2-thenoyl) -o-benzoic acid, melting from 133 to 143 C., was obtained, equal to a yield of 7.5% of theory. After crystallization from 50 parts of high boiling gasoline and 5 parts of toluene, a pure bromo-(2-thenoyl)-o-benzoic acid, melting at 145.5-146 C., was obtained.

In the above examples, the halogenated phthalic anhydrides may be dissolved or suspended in other solvents than benzene. The solvent, however, should be one which does not react upon the Grignard reagent. Ethers other than the diethyl ether may also be used, and the amount of ether employed may be varied within wide limits.

To obtain maximum yields, it has been found that the Grignard reagent should be added to the solution of suspensions of the halogenated phthalic anhydrides. The time of addition may be varied widely, and is mainly determined by the cooling capacity which is required to maintain the reaction at any .desired temperature. The method for isolating the final halogenated (Z-thenOyD-o-benzoic acids will be dictated by such considerations as whether or not isomers are to be expected, and if so, will have to be separated. In case a separation of isomers is required, it has been found most convenient to accomplish it by acidifying their salt solutions first with weak acids, such as acetic acid, then with strong mineral acids like sulfuric acid.

In the case of the 3,6-dichlorophthalic anhydride or the 3,4,5,6-tetrachlorophthalic anhydride, the corresponding halogen (2-thenoyl)-obenzoic acids are obtained free from isomers. In other cases where unsymmetrical halogenated phthalic anhydrides are used, two isomers are usually formed because. both -CO groups of the phthalic anyhdride appear to be reactive, regardless of the position of the substituent halogen.

We claim:

1. The halogen-substituted benzoic acids of the formula:

(Z-thenoyl) -oand 6 a halogen of the group consisting of chlorine and bromine and which carry the same halogen in these positions when more than one position is halogen-substituted.

2. A mono-chloro-(2-thenoyl)-o-benzoic acid of the formula:

5 l I o s 3 g in which the chlorine substituent is in one of the positions 3, 4, 5, and. 6 while the remaining positions are substituted with hydrogen.

3. A mono-bromo-(2-thenoyl) -o-benzoic acid of the formula:

6 COOH Ii /o in which the bromine substituent is in one of the positions 3, 4, 5, and 6 while the remaining positions are substituted with hydrogen.

HENRY R. LEE. VIKTOR WEINMAYR.

REFERENCES CITED The following references are of record in the file of this patent:

Thomas Anhydrous Aluminum Chloride, pages 540, 543, 544 and 547. Reinhold Pub. Co., 1941- 

1. THE HALOGEN-SUBSTITUED (2-THENOYL)-OBENZOIC ACIDS OF THE FORMULA: 